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A new perspective on metabolic alkalosis

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A comprehensive review of metabolic alkalosis for medical students and deep learners

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A new perspective on metabolic alkalosis

  1. 1. A New Perspective on Metabolic alkalosis Taipei Veterans General Hospital, Hsin-Chu branch Director of Nephrology Steve Chen HCO3-
  2. 2. Analysis of Acid-Base Disorders
  3. 3. Na+ NHE-3 H+ HCO3- Na+ NBC H2O CO2+ CA-2 Na+ K+ Na/K ATPase PCT: ↓ Re-absorption of HCO3- H+HCO3-
  4. 4. H+ ATP ase H+ H2O OH- CO2 HCO3- + Cl- CA CCD: ↓ H+ secretion AE-1 α - intercalated cell
  5. 5. CCD: ↑ HCO3- secretion  generation Pendrin β intercalated cell
  6. 6. TYPES OF ACID-BASE DISTURBANCES Depression of the central nervous system, as evidenced by disorientation followed by coma Excitability of the nervous system; muscles may go into a state of tetany and convulsions
  7. 7. Shift of hydrogen ions into the intracellular space Hypokalemia
  8. 8. Na+ NHE-3 H+ HCO3- Na+ NBC H2O CO2+ CA-2 Na+ K+ Na/K ATPase Intracellular acidosis ► ↑ Re-absorption of HCO3- in PCT H+HCO3-
  9. 9. H+ ATP ase H+ H2O OH- CO2 HCO3- + Cl- CA Hypokalemia ► ↑H+ ATPase in CCD AE-1
  10. 10. Hypokalemia ►↓ Cl re-absorption in DCN TSCNa Cl V2R Inactive TSC dimer TSC monomer AT1R MR SPAK TSC: Thiazide Sensitive Co-transporter
  11. 11. Hypokalemia  Metabolic alkalosis • Hypokalemia results in the shift of hydrogen ions intracellularly. The resulting intracellular acidosis enhances bicarbonate re-absorption in the collecting duct • Hypokalemia stimulates the apical H+/K+ ATPase in the collecting duct • Hypokalemia stimulates renal ammonia genesis and alpha- ketoglutarate is produced, the metabolism of which generates bicarbonate that is returned to the systemic circulation • It leads to impaired chloride ion re-absorption in the distal nephron. This results in an increase in luminal electro- negativity, with subsequent enhancement of hydrogen ion secretion
  12. 12. Cortisone excess Cushing syndrome
  13. 13. Aldosterone ►Hypokalemia in CCD E Na C ROMK Na K ATP ase Depolarize + Aldosterone + Na K H Principal cell
  14. 14. Competitive affinity for MR Cortisol >> Aldosterone > cortisone E Na C ROMK Na K ATP ase Depolarize Na K H Aldosterone MR: Mineralocorticoid receptor
  15. 15. Gastrointestinal H+ loss Vomiting or NG suction Antacids in advanced renal failure Renal H+ loss Primary mineralocorticoid excess Post-hypercapnic alkalosis Hypercalcemia (milk-alkali syndrome) Intracellular shift of H+ Hypokalemia / Hypomagnesemia Alkali administration Excess CPR (Ringer lactate) Excess transfusion(citrate blood) Contraction alkalosis (Loss of bicarbonate-poor, chloride-rich extracellular fluid) Loop or thiazide diuretics Bartter or Gitelman syndrome Sweat loss in cystic fibrosis Villous adenoma(Chronic chloride diarrhea )or factitious diarrhea(Laxative abuse) ∆HCO3- < 2~4 meq/L
  16. 16. ROMK - intracellular magnesium Huang et al: JASN 2007 (University of Texas Medical Center) • CCT E Na C ROMK Na K ATP ase UK 5mM CK 143mM Na K Mg
  17. 17. Hypokalemia in magnesium deficiency Huang et al: JASN 2007 (University of Texas Medical Center) • CCT E Na C ROMK Na K ATP ase Urine Blood Na K
  18. 18. Gastrointestinal H+ loss Vomiting or NG suction Antacids in advanced renal failure Renal H+ loss Primary mineralocorticoid excess Post-hypercapnic alkalosis Hypercalcemia (milk-alkali syndrome) Intracellular shift of H+ Hypokalemia / Hypomagnesemia Alkali administration Excess CPR (Ringer lactate) Excess transfusion(citrate blood) Contraction alkalosis (Loss of bicarbonate-poor, chloride-rich extracellular fluid) Loop or thiazide diuretics Bartter or Gitelman syndrome Sweat loss in cystic fibrosis Chronic chloride diarrhea (AR) ∆HCO3- < 2~4 meq/L
  19. 19. Chloride depletion, even without volume depletion, enhances bicarbonate re-absorption • In the late thick ascending limb (THAL) and early distal tubule, specialized cells called the macula densa are present • Na+/K+/2Cl- cotransporter in the apical membrane, which is mainly regulated by chloride ions • When fewer chloride ions reach this transporter (eg, chloride depletion), the macula densa signals the juxtaglomerular apparatus (ie, specialized cells in the wall of the adjacent afferent arteriole) to secrete renin, which increases aldosterone secretion via angiotensin II ( ↑RAA ).
  20. 20. Chloride sensor in macula densa Renin ↑
  21. 21. Bartter’s syndrome in THAL NKCC ROMK Na K ATP ase Na/K K 2Cl CaSR Negative Positive ClC-Kb ClC-KB
  22. 22. Variants of Bartter’s syndrome Israel Zelikovic, NDT 18: 1696-1700, 2003 Defective transporter/protein Clinical Locus Type I NKCC2 (TAL) Antenatal 15q Type II ROMK (TAL/CD) Antenatal 11q Type III ClC-Kb (TAL,DCT) Classic 1p36 Type IV Barttin (β of CIC- Ka/CIC-Kb) BSND (Deafness) 1p31 AD Hypercalciuria CaSR (PT/TAL/DCT/CD) Hypocalcemia 3q
  23. 23. Gitelman’s syndrome in DCT TSC Na Cl V2R Inactive TSC dimer TSC monomer AT1R MR SPAK FE-Cl > 0.5% Hypocalciuria: Ca/Cr < 0.07 (mg/mg)
  24. 24. Gitelman’s / Bartter’s syndrome Gitelman’s Bartter’s Molecular level ↓TSC in DCT ↓NKCC, ROMK, or Cl Age at onset Teenage Children Clinical Tetany Failure to thrive Mimicked by Thiazides Loop diuretics Plasma Mg ↓ ↓ D.D. Hypocalciuria Hypercalciuria Uosm ↓
  25. 25. Check urine Cl-
  26. 26. Low urine chloride ( < 20 meq/L) High urine chloride (> 20 meq/L) Chloride responsive Remote diuretic Vomiting/NG suction Congenital chloridorrhea: AR Villous adenoma (rare) Cystic fibrosis S/P Chronic hypercaria Chloride unresponsive Recent diuretic Severe K depletion High BP Primary hyperaldosteronism Cushing’s disease Ectopic ACTH production Exogenous mineralocorticoids Mineralocorticoid like substance Liddle’s syndrome Low BP Bartter’s syndrome Gitelman’s syndrome
  27. 27. HTN 11β- HSD2D
  28. 28. 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2): cortisolcortisone allow Aldosterone free access to MR in CCD E Na C ROMK Na K ATP ase Depolarize Na K H Aldosterone MR: Mineralocorticoid receptor
  29. 29. 11-beta-hydroxysteroid dehydrogenase type 2 (11B-HSD2) deficiency • AR • Syndrome of apparent mineralocorticoid excess (AME) • Hypertension with low renin and low aldosterone, hypokalemia, and metabolic alkalosis • Serum cortisol is within the reference range because the negative feedback of cortisol on adrenocorticotropic hormone (ACTH) is intact. • The enzyme may be inhibited by glycyrrhizic acid, which is found in licorice and chewing tobacco, or carbenoxolone, which is a synthetic derivative of glycyrrhizinic acid
  30. 30. HTN GRH
  31. 31. Glucocorticoid-remediable aldosteronism an autosomal dominant disorder, in which ectopic production of aldosterone in the zona fasciculata of the adrenal cortex occurs
  32. 32. Simple or mixed ? Conditions Primary event Secondary response Metabolic acidosis (30 minutes onset, 12-24H completion) HCO3 ↓ 1 meq/L pCO2 ↓ 1.2 mmHg Metabolic alkalosis (30 minutes onset, 12-24H completion) HCO3 ↑ 1 meq/L pCO2 ↑ 0.7 mmHg Respiratory acidosis Acute Chronic > 3-5days pCO2 ↑ 10 mmHg HCO3 ↑ 1 meq/L ↑ 3.5-4 meq/L Respiratory alkalosis Acute Chronic >3-5 days pCO2 ↓ 10 mmHg HCO3 ↓ 2 meq/L ↓ 4-5 meq/L
  33. 33. General Principles of Treatment  ↑ Renal bicarbonate excretion ( urine pH>7 ) A reduced effective arterial blood volume (EABV) Chloride depletion (hypochloremia) Potassium depletion (hypokalemia)  K supply  All exogenous sources of alkali should be discontinued: Citrate/Ketones/Lactate  Drugs that reduce gastric HCl secretion. H2 blockers PPI NS
  34. 34. General Principles of Treatment  Acetazolamide(250-500mg/D) is a carbonic anhydrase inhibitor that preferentially inhibits proximal sodium bicarbonate reabsorption  Potassium-sparing diuretics  NH4Cl ( 100 meq/L/ 20 mL vial) 1-2 vials in 1000 mL of NS

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